Molecular analysis of plasma DNA during human pregnancy has led to the discovery of fetal transcript. This valuable source of fetal transcript opens up new avenue for noninvasive prenatal diagnosis and evaluation of complication of pregnancy. Circulating DNA has been shown to have application in prenatal diagnosis of fetal rhesus D status, sex-linked disorder, and other paternally inherited genetic disorders. However, it only allows examination of disorders where the gene of interest is present in the fetal genome but absent from maternal DNA. Since most of fetal DNA probably originates from villous trophoblast, concentrations can be used to evaluate damage to trophoblasts, particularly in pathologic complication of pregnancy such as preeclampsia, invasive placenta, hyperemesis gravidarum, and trisomy 21. However, even several centers have used circulating fetal DNA for clinical setting, its biology and mechanisms are far from being well understood. It remains much to be learned about the biology of this phenomenon for additional diagnostic applications which can be expected in the near future.